Interaction of macrocyclic gadolinium-based MR contrast agents with Type I collagen. Equilibrium and kinetic studies

Guidolin, Nicol; Travagin, Fabio; Giovenzana, Giovanni B.; Vágner, Adrienn; Lotti, Sophia; Chianale, Federica; Brücher, Ernő; Maisano, Federico; Kirchin, Miles A.; Tedoldi, Fabio; Giorgini, Alice; Serra, Sonia Colombo; Baranyai, Zsolt

doi:10.1039/d0dt03314f

Cited by 8 publications

(11 citation statements)

References 38 publications

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“…Given that skin is a collagenrich tissue, this finding is consistent with findings from a recent in vitro study, which showed that gadoteridol accumulates to a lower degree in collagen than both gadoterate and gadobutrol. 23 Our findings for the skin are also consistent with those from a previous study of long-term Gd retention in the skin of rats, 24 which indicated considerably lower levels of retained Gd at early timepoints after a cumulative dose of 12.5 mmol/kg bodyweight (approximately 23 nmol Gd/g skin for gadoteridol at 3 days after the end of dosing compared to 50-60 nmol Gd/g skin for gadoterate and gadobutrol). Consistent with our findings, they showed that by day 35 after the end of dosing, the Gd levels in the skin were lower for gadoteridol (1 AE 1 nmol Gd/g), than for both gadoterate and gadobutrol (2 AE 1 nmol Gd/g).…”

Section: Discussionsupporting

confidence: 91%

“…This possibly reflects faster clearance of gadoteridol immediately after the GBCA administration phase. Given that skin is a collagen‐rich tissue, this finding is consistent with findings from a recent in vitro study, which showed that gadoteridol accumulates to a lower degree in collagen than both gadoterate and gadobutrol 23 . Our findings for the skin are also consistent with those from a previous study of long‐term Gd retention in the skin of rats, 24 which indicated considerably lower levels of retained Gd at early timepoints after a cumulative dose of 12.5 mmol/kg bodyweight (approximately 23 nmol Gd/g skin for gadoteridol at 3 days after the end of dosing compared to 50–60 nmol Gd/g skin for gadoterate and gadobutrol).…”

Section: Discussionsupporting

confidence: 90%

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Gadolinium Clearance in the First 5 Weeks After Repeated Intravenous Administration of Gadoteridol, Gadoterate Meglumine, and Gadobutrol to rats

Bussi

Coppo

Bonafè

et al. 2021

Magnetic Resonance Imaging

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Background Studies of gadolinium (Gd) clearance from animals in the first weeks after administration of gadolinium‐based contrast agents (GBCAs) have previously looked at solitary timepoints only. However, this does not give information on differences between GBCAs and between organs in terms of Gd elimination kinetics. Purpose To compare Gd levels in rat cerebellum, cerebrum, skin, and blood at 1, 2, 3, and 5 weeks after repeated administration of macrocyclic GBCAs. Study Type Prospective. Animal Model One hundred eighty male Sprague–Dawley rats randomized to three groups (n = 60/group), received intravenous administrations of gadoteridol, gadoterate meglumine, or gadobutrol (0.6 mmol/kg for each) four times/week for 5 consecutive weeks. Rats were sacrificed after washout periods of 1, 2, 3, or 5 weeks. Field Strength/Sequence Not applicable. Assessment Cerebellum, cerebrum, skin, and blood were harvested for Gd determination by inductively coupled plasma‐mass spectrometry (15 animals/group/all timepoints). Statistical Tests Anova and Dunnett's test (data with homogeneous variances and normal distribution). Kruskal–Wallis and Wilcoxon's rank sum tests (data showing nonhomogeneous variances or a non‐normal distribution, significance levels: P < 0.05, P < 0.01, and P < 0.001). Results Gd levels in cerebellum, cerebrum, and skin were significantly lower after gadoteridol than after gadoterate and gadobutrol at all timepoints. Mean cerebellum Gd concentrations after gadoteridol, gadoterate, and gadobutrol decreased from 0.693, 0.878, and 1.011 nmol Gd/g at 1 week to 0.144, 0.282, and 0.297 nmol Gd/g at 5 weeks after injection. Similar findings were noted for cerebrum and skin. Conversely, significantly higher Gd levels were noted in blood after gadoteridol compared to gadobutrol at 1, 2, and 3 weeks and compared to gadoterate at all timepoints. Data Conclusion Gadoteridol is eliminated more rapidly from rat cerebellum, cerebrum, and skin compared to gadoterate and gadobutrol in the first 5 weeks after administration, resulting in lower levels of retained Gd in these tissues. Evidence Level 1 Technical Efficacy Stage 5

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

Gadolinium Clearance in the First 5 Weeks After Repeated Intravenous Administration of Gadoteridol, Gadoterate Meglumine, and Gadobutrol to rats

Bussi

Coppo

Bonafè

et al. 2021

Magnetic Resonance Imaging

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“…In common with other tissues evaluated, greater levels of retained Gd were noted with gadobutrol and gadoterate than with gadoteridol: at day 28 after treatment, the Gd content in peripheral nerves of SN rats treated with gadobutrol or gadoterate was 5.4 and 7.2 times higher, respectively, than in SN rats treated with gadoteridol. Considering that collagen is the main component of the extracellular matrix of peripheral nerves (comprising about 90% type I collagen [ 34 , 35 ]), our findings are consistent with those of a recent in vitro study, which showed that gadoteridol accumulates to a lower degree in collagen than both gadoterate and gadobutrol [ 36 ]. Our study also demonstrated that Gd content was higher in peripheral nerves than in both the cerebrum and cerebellum, particularly at day 28 after treatment.…”

Section: Discussionsupporting

confidence: 90%

Gadolinium retention in a rat model of subtotal renal failure: are there differences among macrocyclic GBCAs?

et al. 2023

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Background Gd levels are higher in tissues of animals with compromised renal function, but studies to compare levels after exposure to different macrocyclic gadolinium-based contrast agents (GBCAs) are lacking. We compared Gd levels in tissues of subtotally nephrectomised (SN) rats after repeated exposure to macrocyclic GBCAs. Methods Sprague–Dawley SN male rats (19 per group) received 16 injections of gadoteridol, gadobutrol, or gadoterate meglumine at 0.6 mmol Gd/kg 4 times/weeks over 4 weeks. A control group of healthy male rats (n = 10) received gadoteridol at the same dosage. Plasma urea and creatinine levels were monitored. Blood, cerebrum, cerebellum, liver, femur, kidney(s), skin and peripheral nerves were harvested for Gd determination by inductively coupled plasma-mass spectrometry at 28 and 56 days after the end of treatment. Results Plasma urea and creatinine levels were roughly twofold higher in SN rats than in healthy rats at all timepoints. At day 28, Gd levels in the peripheral nerves of gadobutrol- or gadoterate-treated SN animals were 5.4 or 7.2 times higher than in gadoteridol-treated animals (p < 0.001). Higher Gd levels after administration of gadobutrol or gadoterate versus gadoteridol were also determined in kidneys (p ≤ 0.002), cerebrum (p ≤ 0.001), cerebellum (p ≤ 0.003), skin (p ≥ 0.244), liver (p ≥ 0.053), and femur (p ≥ 0.271). At day 56, lower Gd levels were determined both in SN and healthy rats for all GBCAs and tissues, except the femur. Conclusions Gd tissue levels were lower following gadoteridol exposure than following gadobutrol or gadoterate exposure.

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“…Therefore, the observations may not represent a clinical scenario. The mechanism by which macrocyclic agents would be retained is unknown, although a recent report on interaction of macrocyclic GBCAs with collagen [ 86 ] suggests that binding of intact macrocyclic complexes to components of the extracellular matrix may account for the retention of intact macrocyclic GBCAs complexes. This study showed that all macrocyclic agents have similar affinity to collagen type I, but the maximum amount of collagen bound was slightly different: it decreased following the order of gadoterate meglumine > gadobutrol > gadoteridol.…”

Section: What Prediction Can We Make About Gadolinium Deposition? How Do Those Predictions Relate To Preclinical Results?mentioning

confidence: 99%

How the Chemical Properties of GBCAs Influence Their Safety Profiles In Vivo

2021

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The extracellular class of gadolinium-based contrast agents (GBCAs) is an essential tool for clinical diagnosis and disease management. In order to better understand the issues associated with GBCA administration and gadolinium retention and deposition in the human brain, the chemical properties of GBCAs such as relative thermodynamic and kinetic stabilities and their likelihood of forming gadolinium deposits in vivo will be reviewed. The chemical form of gadolinium causing the hyperintensity is an open question. On the basis of estimates of total gadolinium concentration present, it is highly unlikely that the intact chelate is causing the T1 hyperintensities observed in the human brain. Although it is possible that there is a water-soluble form of gadolinium that has high relaxitvity present, our experience indicates that the insoluble gadolinium-based agents/salts could have high relaxivities on the surface of the solid due to higher water access. This review assesses the safety of GBCAs from a chemical point of view based on their thermodynamic and kinetic properties, discusses how these properties influence in vivo behavior, and highlights some clinical implications regarding the development of future imaging agents.

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Interaction of macrocyclic gadolinium-based MR contrast agents with Type I collagen. Equilibrium and kinetic studies

Abstract: The interactions of gadoterate meglumine, gadobutrol, gadoteridol and Gd(HB-DO3A) with bovine Type I collagen were investigated by ultrafiltration and dialysis. The affinity of the four agents to collagen is rather...

Cited by 8 publications

References 38 publications

Gadolinium Clearance in the First 5 Weeks After Repeated Intravenous Administration of Gadoteridol, Gadoterate Meglumine, and Gadobutrol to rats

Gadolinium Clearance in the First 5 Weeks After Repeated Intravenous Administration of Gadoteridol, Gadoterate Meglumine, and Gadobutrol to rats

Gadolinium retention in a rat model of subtotal renal failure: are there differences among macrocyclic GBCAs?

How the Chemical Properties of GBCAs Influence Their Safety Profiles In Vivo

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